Gastric adenocarcinoma and periodontal disease: A systematic review and meta-analysis

Highlights • Patients presenting periodontal disease increased the risk of developing gastric adenocarcinoma by 17 %.• The association remained regardless of the diagnostic method for periodontal disease, i.e., clinical examination and self-report.• Moreover, Asian patients with periodontal disease had a higher risk of having gastric adenocarcinoma than American and European patients.


Introduction
In 2020, Gastric Cancer (GC) was the malignancy that had more than one million new cases and about 770,000 deaths worldwide.Being it is fifth most frequent cancer and the fourth cause of cancer death in the world. 1 Its risk factors already known, in addition to infection by Helicobacter pylori (H.pylori), are obesity, excessive intake of salt and meat, low consumption of fruits and vegetables, smoking, alcoholism, and low socioeconomic status, they are associated with gastric carcinoma and other malignancies. 2,3riodontal diseases affect up to 50 % of the world's population and rank sixth among the most prevalent pathologies worldwide. 4Alterations in oral dysbioses change the oral microbiome, which may lead to oral pathologies such as Periodontal Disease (PD).Gingivitis and periodontitis are the most common forms of PD.This disease has different clinical signs of inflammation limited to the gum (gingivitis), while periodontitis results in progressive destruction of the periodontal ligament and alveolar bone, forming pouch, gingival retraction, or both 5,6 and tooth loss is considered a result a significant increase in periodontal diseases in individuals over 40 years of age. 7Therefore, there is some evidence about that dysbiosis occurring in the oral cavity, such as periodontal disease, is a trigger for cancer, such as gastric adenocarcinoma. 8,9−18 This study aimed to conduct a systematic review with meta-analysis to investigate the an association between PD and GAC.

Materials and methods
This project was registered on the International Prospective Register of Systematic Reviews -PROSPERO platform on January 18, 2021, under registration code CRD42021221317.

Literature search
This systematic review was conducted and reported in accordance with PRISMA guidelines. 19Articles were identified through searches limited to the English language on the PubMed, Embase, Web of Science, Scopus, Lilacs and Opengrey databases.The search strategy was based on different terms for each database (Table 1).

Study selection
In this study, the presence of PD was considered whether, at least, one of these clinical characteristics occurs: gingivitis, periodontitis and tooth loss. 5,20This systematic review included case-controls and cohorts studies, and the authors excluded cross-sectional, experimental, animal studies, and case reports.Thus, the authors used the Rayyan software to identify eligible studies and exclude duplicates. 21The researchers (FJNA and MAF) retrieved data from studies independently based on titles and abstracts of the eligible studies according to the question of the systematic review (Are patients with periodontal disease at risk for developing gastric adenocarcinoma?).Moreover, references of the selected articles were reviewed to find relevant studies.

Data extraction
The following variables were collected: (1) First author, year of the publication, and place of the study; (2)   2 and 3).The discrepancies between the two reviewers were solved with the participation of a third evaluator (FSM).

Risk of bias
The Newcastle-Ottawa Scale (NOS) was applied to evaluate the quality of selected studies, by two independent, previously trained and approved reviewers.The methodological is divided into three components: group selection (0-4 points), quality of adjustment for confounding (0-2 points), and exposure assessment after outcome (0-3 points).The maximum score can be 9 points, which represents high methodological quality. 22A the funnel plot was carried out to assess the risk of publication bias. 23

Statistical analysis
For this meta-analysis, the authors considered the following measures of association: Odds Ratio (OR); Relative Risk (RR): Hazard Ratio (HR) and their respective 95 % Confidence Intervals (95 % CI).Accordingly, the authors carried out fixed and random effects models using the "metan" command. 24The heterogeneity among the studies was assessed by the I 2 statistic, where I 2 = 0-25 % indicated low heterogeneity; I 2 = 25 %-50 %, moderate heterogeneity; and I 2 > 50 %, high heterogeneity. 25The authors used the random effects model in case of high heterogeneity among studies and the software to perform the meta-analysis was STATA 15.

Study selection
The authors have found 639 articles between 1961 and 2022 (Fig. 1).After reading their title/abstract, the study excluded 441.From that 40 articles were considered eligible for a full reading.Seven studies were shortlisted for the meta-analysis, 16,26−31 two additional articles were included. 32,33Thus, nine articles were included in this systematic review, three case control studies 26,27,32 and six cohort studies 16,[28][29][30][31]33 published between 1998 and 2018.The authors found a population of 2884 cases patients with GAC in the nine studies included.
About six studies were carried out in Asia accounting 2280 gastric adenocarcinoma cases and the diagnostic criteria for PD was the clinical examination (Tables 2 and 3).
In cohort studies, the NOS ranged from eight points 30,33 to nine points, 16,28,29,31 and between six and eight points 26,27,32 among casecontrol studies selected therefore selected studies have high scores in quality (Fig. 2).
In cohort studies, the NOS ranged from eight points 30,33 to nine points.

Summary of meta-analysis
In the meta-analysis of nine observational studies, the presence of PD was associated to an increase in the risk of GAC by 17 % (RR = 1.17; 95 % CI 1.03-1.32),with a heterogeneity of 39.9 % (Fig. 3).While in the subgroup analysis, cohort and case-control studies had no association with PD and GAC (Fig. 4).
An association between GAC and PD was found to be a risk in the Asian population (RR = 1.17; 95 % CI 1.00-1.36);however, in American and European studies there was no risk (RR = 1.18; 95 % CI 0.84-1.66)(Fig. 5).
To evaluate the presence of PD In epidemiological studies, it can be assessed by patient self-report and by clinical examination.The authors observed an increased risk of patients with PD presenting GAC, that remained regardless of the diagnostic method for PD, 19 % (RR=1.19; 95% CI 1.14-1.24)to 34 % (RR = 1.34; 95 % CI 1.06-1.69)for clinical examination and self-report, respectively (Fig. 6).
No publication bias was observed in the selected studies according to the Egger test (p = 0.860) (Fig. 7).

Discussion
To our knowledge, this is the first meta-analysis to explore the association of PD with the risk of GAC.In this study, patients with PD were at risk of developing GAC, which validates the hypothesis that PD is proposed as a potential carcinogenic factor. 16The authors also observed that the risk for GAC continues regardless of the diagnostic method for PD.However, there were differences between populations; Asian patients were at risk of developing GAC associated with PD than Americans and Europeans.It is necessary to point out that the studies had several adjustment variables: Sex; Smoking; Alcohol; socioeconomic status;  CI, confidence interval; F, female; M, male; CG, gastric cancer; OR, odds ratio; RR, relative risk; HR, hazard ratio; BMI, body mass index; COPD, chronic obstructive pulmonary disease; ICD, international classification of diseases.CI, confidence interval; F, female; M, male; CG, gastric cancer; OR, odds ratio; RR, relative risk; HR, hazard ratio; BMI, body mass index; COPD, chronic obstructive pulmonary disease; DHF, international classification of diseases; DMFT, decayes, missing and filled teeth.Intake of vegetables and fruits; BMI; Regular physical activity.Therefore, the present results highlight that periodontal diseases have a significant effect on GAC, further studies are needed to assess how this mechanism occurs and which other microorganisms may be linked to oral-gastric dysbiosis.Gastric cancer is the leading cause of death among men in South Asian countries. 1This study found an association between periodontal disease and gastric adenocarcinoma in Asian studies, as opposed to American and European studies.Asian populations have polymorphisms of the interleukin genes (IL-17 and IL-10) that increase the risk of gastric cancer, due to their interaction with H. pylori and the habit of smoking. 34hese same genetic polymorphisms can cause phenotypic differences in the inflammatory responses in PD, which are important in the individual's sensitivity to the disease, in the progression of the disease or in the response to treatment. 35The prevalence of PD varies between 16 % (Western Pacific region) and 23 % (Africa region), while case numbers reflect the demographic share of the respective regions, with Southeast Asia and Western Pacific regions having the highest number of cases and the Eastern Mediterranean region with the lowest number of PD cases. 4he gold standard for evaluating PD is probing all teeth and radiographic interpretation. 36,37−41 In this meta-analysis, the authors observed an increased risk of PD patients developing GAC, regardless of the diagnostic method used for PD.
This meta-analysis presents limitations.−33 In addition to what studies use as a proxy for PD (gingivitis, periodontitis and tooth loss), therefore, the authors included it in the systematic review.However, it has strength as many participants providing accurate risk estimates, and a high methodological quality of the selected studies.Furthermore, the sensitivity analysis identified that patients with PD may be associated with the development of GAC, regardless of the diagnostic method for PD.
Since there is not enough evidence demonstrating how this association between PD and risk of GAC occurs.Additional studies with more detailed PD data and assessment of the oral microbiome may provide more clarity.

Conclusion
The presence of PD increased the risk of GAC.Several studies suggest that the infectious-inflammatory process of PD can initiate complex reactions involving inflammation mediators and microorganisms that may link the risk of tumor development, therefore there are biological bases to support a relationship between PD and GAC, but more studies are needed to assess the depth of this connection.In addition to considering the screening of patients at potential risk for GAC in the clinical practice of dentists.

Fig. 1 .
Fig. 1.Prisma Selection of eligible studies for the systematic review.

Fig. 2 .
Fig. 2. Evaluation of the methodological quality of case-control and cohort studies according to the Newcastle -Ottawa Scale (Wells et al., 2014).

Fig. 3 .
Fig. 3. Forest plot of cohort and case-control studies between periodontal disease and gastric adenocarcinoma (Random model).

Fig. 4 .
Fig. 4. Forest plot of cohort (A) and case-control (B) studies between periodontal diseases and gastric adenocarcinoma (Random model).

Fig. 5 .
Fig. 5. Forest plot of Asian (A) and American and European (B) studies between periodontal diseases and gastric adenocarcinoma (Random model).

Fig. 7 .
Fig. 7. Funnel plot of all studies included in the meta-analysis.

Table 1
Search strategy.
0 Web of science www.webofknowledge.comTI=(cancer) AND TS=(periodontal* diseases OR gingivitis OR periodontitis OR tooth* loss AND gastric cancer*) AND AB=(stomach cancer OR gastric cancer AND periodontal disease OR gingivitis OR periodontitis OR tooth loss) AND TI=(stomach cancer OR gastric cancer AND periodontal disease OR gingivitis OR periodontitis OR tooth loss) 75 OpenGrey http://www.opengrey.eu"periodontal disease" OR "gingivitis" OR "periodontitis" OR "tooth loss" AND "gastric" 0 2 F.J.N.Aguiar et al.Clinics 79 (2024) 100321

Table 2
Characteristics of the case-control studies included in the systematic review.

Table 3
Characteristics of cohort studies included in the systematic review.